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Development of a long-acting relaxin analogue, LY3540378, for treatment of chronic heart failure. 2023

Petra Verdino, and Stacey L Lee, and Fariba N Cooper, and Steven R Cottle, and Patrick F Grealish, and Charlie C Hu, and Catalina M Meyer, and Joanne Lin, and Victoria Copeland, and Gina Porter, and Richard L Schroeder, and Tyran D Thompson, and Leah L Porras, and Asim Dey, and Hong Y Zhang, and Emily C Beebe, and Scot J Matkovich, and Tamer Coskun, and Aldona M Balciunas, and Andrea Ferrante, and Robert Siegel, and Laurent Malherbe, and Nicoletta Bivi, and Chad D Paavola, and Ryan J Hansen, and Matthew M Abernathy, and Sylvia O Nwosu, and Molly C Carr, and Josef G Heuer, and Xiaojun Wang
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.

Chronic heart failure, a progressive disease with limited treatment options currently available, especially in heart failure with preserved ejection fraction (HFpEF), represents an unmet medical need as well as an economic burden. The development of a novel therapeutic to slow or reverse disease progression would be highly impactful to patients and society. Relaxin-2 (relaxin) is a human hormone regulating cardiovascular, renal, and pulmonary adaptations during pregnancy. A short-acting recombinant relaxin, Serelaxin, demonstrated short-term heart failure symptom relief and biomarker improvement in acute heart failure trials. Here, we present the development of a long-acting relaxin analogue to be tested in the treatment of chronic heart failure. LY3540378 is a long-acting protein therapeutic composed of a human relaxin analogue and a serum albumin-binding VHH domain. LY3540378 is a potent agonist of the relaxin family peptide receptor 1 (RXFP1) and maintains selectivity against RXFP2/3/4 comparable to native relaxin. The half-life of LY3540378 in preclinical species is extended through high affinity binding of the albumin-binding VHH domain to serum albumin. When tested in a single dose administration, LY3540378 elicited relaxin-mediated pharmacodynamic responses, such as reduced serum osmolality and increased renal blood flow in rats. In an isoproterenol-induced cardiac hypertrophy mouse model, treatment with LY3540378 significantly reduced cardiac hypertrophy and improved isovolumetric relaxation time. In a monkey cardiovascular safety study, there were no adverse observations from administration of LY3540378. LY3540378 demonstrated to be a suitable clinical development candidate, and is progressing in clinical trials.

UI MeSH Term Description Entries
D011247 Pregnancy The status during which female mammals carry their developing young (EMBRYOS or FETUSES) in utero before birth, beginning from FERTILIZATION to BIRTH. Gestation,Pregnancies
D012065 Relaxin A water-soluble polypeptide (molecular weight approximately 8,000) extractable from the corpus luteum of pregnancy. It produces relaxation of the pubic symphysis and dilation of the uterine cervix in certain animal species. Its role in the human pregnant female is uncertain. (Dorland, 28th ed) Relaxin B
D005260 Female Females
D006331 Heart Diseases Pathological conditions involving the HEART including its structural and functional abnormalities. Cardiac Disorders,Heart Disorders,Cardiac Diseases,Cardiac Disease,Cardiac Disorder,Heart Disease,Heart Disorder
D006332 Cardiomegaly Enlargement of the HEART, usually indicated by a cardiothoracic ratio above 0.50. Heart enlargement may involve the right, the left, or both HEART VENTRICLES or HEART ATRIA. Cardiomegaly is a nonspecific symptom seen in patients with chronic systolic heart failure (HEART FAILURE) or several forms of CARDIOMYOPATHIES. Cardiac Hypertrophy,Enlarged Heart,Heart Hypertrophy,Heart Enlargement,Cardiac Hypertrophies,Enlargement, Heart,Heart Hypertrophies,Heart, Enlarged,Hypertrophies, Cardiac,Hypertrophies, Heart,Hypertrophy, Cardiac,Hypertrophy, Heart
D006333 Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (VENTRICULAR DYSFUNCTION), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as MYOCARDIAL INFARCTION. Cardiac Failure,Heart Decompensation,Congestive Heart Failure,Heart Failure, Congestive,Heart Failure, Left-Sided,Heart Failure, Right-Sided,Left-Sided Heart Failure,Myocardial Failure,Right-Sided Heart Failure,Decompensation, Heart,Heart Failure, Left Sided,Heart Failure, Right Sided,Left Sided Heart Failure,Right Sided Heart Failure
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D013318 Stroke Volume The amount of BLOOD pumped out of the HEART per beat, not to be confused with cardiac output (volume/time). It is calculated as the difference between the end-diastolic volume and the end-systolic volume. Ventricular Ejection Fraction,Ventricular End-Diastolic Volume,Ventricular End-Systolic Volume,Ejection Fraction, Ventricular,Ejection Fractions, Ventricular,End-Diastolic Volume, Ventricular,End-Diastolic Volumes, Ventricular,End-Systolic Volume, Ventricular,End-Systolic Volumes, Ventricular,Fraction, Ventricular Ejection,Fractions, Ventricular Ejection,Stroke Volumes,Ventricular Ejection Fractions,Ventricular End Diastolic Volume,Ventricular End Systolic Volume,Ventricular End-Diastolic Volumes,Ventricular End-Systolic Volumes,Volume, Stroke,Volume, Ventricular End-Diastolic,Volume, Ventricular End-Systolic,Volumes, Stroke,Volumes, Ventricular End-Diastolic,Volumes, Ventricular End-Systolic
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus

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